Retinoblastoma

Key points

• Most common intraocular malignancy in children (peak 0-3 years)
• Heritable (germline RB1, ~40%): bilateral, multifocal, earlier onset, second malignancy risk
• Sporadic (~60%): unilateral, unifocal
• Bilateral RB = always heritable until proven otherwise
• Calcified intraocular mass is the hallmark imaging finding (~95%)

Epidemiology & risk factors

• Peak age 0-3 years
• Heritable (~40%): autosomal dominant, germline RB1 mutation (13q14)
• Sporadic (~60%): somatic RB1 mutation, both hits acquired
• Knudson two-hit hypothesis: germline carriers need only one somatic hit
• Heritable form carries lifelong risk of second malignancies (osteosarcoma, soft tissue sarcoma), especially after EBRT

Pathophysiology

• Loss of function of RB1 tumour suppressor gene at 13q14
• RB1 encodes pRb, a key cell cycle regulator (G1/S checkpoint)
• Germline mutation = first hit inherited, second hit somatic; sporadic = both hits somatic

Clinical features

• Leukocoria (white pupillary reflex) - most common presentation
• Strabismus
• Advanced: painful blind eye, proptosis (extraocular extension)
• Metastasis: bone marrow, bone, CNS (leptomeningeal)

Imaging / investigations

Ultrasound (first-line)

• Echogenic intraocular mass with posterior acoustic shadowing (calcification)
• First-line screening tool in ophthalmology clinic

CT

• Calcified intraocular mass - hallmark (~95% calcify)
• Calcification is the key discriminator vs other causes of leukocoria
• Avoid in young children where possible (radiation to lens - cataract risk); reserve for when calcification confirmation changes management

MRI (preferred for staging)

• T1: iso-to-hyperintense to vitreous; T2: hypointense (high cellularity, high N:C ratio)
• Avid enhancement post-gadolinium
• Assess for:
  • Vitreous/subretinal seeding - irregular enhancing deposits
  • Optic nerve invasion - pre-laminar vs post-laminar (prognostically critical; post-laminar = risk of subarachnoid/CNS spread)
  • Choroidal/scleral invasion, extraocular extension
• Screen pineal gland for trilateral RB

Differentials - leukocoria

Staging

ICRB (groups A-E) - predicts eye salvage likelihood:

• A-B: small tumours, no seeding - focal therapy/chemoreduction, high salvage rate
• C-D: vitreous/subretinal seeding - intensive chemo (systemic +/- intra-arterial), salvage attempted
• E: extensive destructive disease - enucleation (no salvage potential)

AJCC TNM - predicts survival/systemic prognosis:

• T3 = choroidal/scleral/optic nerve invasion - worse prognosis
• T4 = extraocular - very poor prognosis

Remember: ICRB = eye salvage, AJCC = survival.

Management

• Group A-D: chemoreduction (systemic/intra-arterial/intravitreal) +/- focal therapy (laser, cryo, thermotherapy)
• Group E / failed salvage: enucleation
• Avoid EBRT in germline RB - high risk of radiation-induced second malignancies in-field
• Enucleation = globe removed, orbital contents preserved
• Evisceration = intraocular contents removed, scleral shell left (not used in RB - tumour seeding risk)
• Exenteration = globe + orbital contents removed (advanced orbital disease)

Trilateral & quadrilateral RB

• Trilateral: bilateral RB + pineoblastoma - screen with MRI at Dx and follow-up
• Quadrilateral: + suprasellar PNET (rare, low exam yield)
• Pineal screening is standard in all bilateral/heritable RB